Necrostatin-1 blocks both RIPK1 and IDO: consequences for the study of cell death in experimental disease models

Vandenabeele, Peter; Grootjans, Sasker; Callewaert, Nico; Takahashi, Nozomi

doi:10.1038/cdd.2012.151

Cited by 150 publications

(122 citation statements)

References 18 publications

Supporting

Mentioning

115

Contrasting

Order By: Relevance

“…Targeting RN pathways depends on the availability of effective pharmacological agents, and net effects in complex disease settings are not fully predictable from expected targets. In this regard, two groups have recently reported that Nec-1 can accelerate time to death in the TNF-shock model (11,28,29). In the present studies, however, concomitant application of Nec-1 to modify necroptosis and SfA to modify the MPT, like the dko mice, provided marked protection from IRI.…”

Section: Discussioncontrasting

confidence: 50%

“…However, existing data that imply protection by interference with necroptosis in various in vivo models used the RIPK1 kinase inhibitor necrostatin (Nec)-1 to inhibit necrotic signaling (10,11,26,27). However, Nec-1 has recently been discussed to directly influence the immune system, besides its effects to block release of CDAMPs (28,29). Therefore, it remains an open question whether necroptosis in IRI is of relevance in the absence of a functional immune system.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Two independent pathways of regulated necrosis mediate ischemia–reperfusion injury

Linkermann

Bräsen

Darding

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

499

456

View full text Add to dashboard Cite

Regulated necrosis (RN) may result from cyclophilin (Cyp)D-mediated mitochondrial permeability transition (MPT) and receptorinteracting protein kinase (RIPK)1-mediated necroptosis, but it is currently unclear whether there is one common pathway in which CypD and RIPK1 act in or whether separate RN pathways exist. Here, we demonstrate that necroptosis in ischemia-reperfusion injury (IRI) in mice occurs as primary organ damage, independent of the immune system, and that mice deficient for RIPK3, the essential downstream partner of RIPK1 in necroptosis, are protected from IRI. Protection of RIPK3-knockout mice was significantly stronger than of CypD-deficient mice. Mechanistically, in vivo analysis of cisplatin-induced acute kidney injury and hyperacute TNF-shock models in mice suggested the distinctness of CypD-mediated MPT from RIPK1/RIPK3-mediated necroptosis. We, therefore, generated CypD-RIPK3 double-deficient mice that are viable and fertile without an overt phenotype and that survived prolonged IRI, which was lethal to each single knockout. Combined application of the RIPK1 inhibitor necrostatin-1 and the MPT inhibitor sanglifehrin A confirmed the results with mutant mice. The data demonstrate the pathophysiological coexistence and corelevance of two separate pathways of RN in IRI and suggest that combination therapy targeting distinct RN pathways can be beneficial in the treatment of ischemic injury.RIP3 | RIP1 | programmed necrosis | apoptosis

show abstract

Section: Discussioncontrasting

confidence: 50%

mentioning

confidence: 99%

Two independent pathways of regulated necrosis mediate ischemia–reperfusion injury

Linkermann

Bräsen

Darding

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

499

456

View full text Add to dashboard Cite

show abstract

“…For example, overexpression of Bcl-2 was found suffi cient to prevent the necrotic death of neuronal and non-neuronal cells (19,20). It has also been reported that RIPK1 can regulate not only necroptotic but also apoptotic cell death (21).…”

Section: Discussionmentioning

confidence: 99%

Quercetin induces apoptosis and necroptosis in MCF-7 breast cancer cells

Khorsandi¹,

Orazizadeh²,

Niazvand³

et al. 2017

BLL

View full text Add to dashboard Cite

OBJECTIVE: This study investigated the quercetin (Que) effects on growth of MCF-7 human cancer breast cell line and its cellular death mechanism. BACKGROUND: Quercetin has been found to be very effi cacious against many different types of cancer cells. However, the study is not suffi ciently powered to demonastrate anticancer mechanisms. METHODS: MCF-7cells were treated by 50 μM/ ml of Que for 48 hours. MCF-7 cells were also pretreated with 10 Μm ZVAD (apoptosis inhibitor) or 3 mM Nec-1 (necroptosis inhibitor) for evaluation of cell death induced by apoptosis or necroptosis. RESULTS: MTT and clonogenicity assays revealed that the Que induced a signifi cant increase in cell viability and proliferation in presence of Nec-1 in comparison to the presence of ZVAD (p < 0.05). Que also increased apoptosis as revealed by DAPI staining and morphology evaluations. Following Que treatment Bcl-2 expression was signifi cantly decreased while Bax expression was signifi cantly increased. Que in presence of Nec-1 decreased expression of Bax gene, reduced apoptotic index, increased cell viability and proliferation of MCF-7 cells in comparison to absence of Nec-1. MCF-7 cells showed a signifi cantly increased expression of RIPK1 and RIPK3 in response to Que plus ZVAD in comparison to absence of ZVAD. CONCLUSION: Our results revealed that the high Que toxicity for breast cancer cells depends on multiple cell death pathways, which involve mainly necroptosis (Fig. 6, Ref. 21). Text in PDF www.elis.sk.

show abstract

“…For example, (i) many proteins are phosphorylated at a specific site only in human proteins (e.g., Ser-46 phosphorylation in human but not mouse p53), (ii) only human endothelial cells but not mouse counterparts express functional CD40, and (iii) HtrA2 cleaves mouse but not human RIP1 (41)(42)(43). In addition, human and mouse cells seem to have different susceptibility levels and responses to RIP1 kinase inhibitor Nec-1 and its inactive control, Nec1i (44). This suggests that it is important to take into account the difference between human and mouse RIP1 when TRAIL's antitumor efficacy is studied in preclinical and clinical trials.…”

Section: Discussionmentioning

confidence: 99%

RIP1 Cleavage in the Kinase Domain Regulates TRAIL-Induced NF-κB Activation and Lymphoma Survival

Zhang

Blackwell

Workman

et al. 2015

Molecular and Cellular Biology

View full text Add to dashboard Cite

Necrostatin-1 blocks both RIPK1 and IDO: consequences for the study of cell death in experimental disease models

Cited by 150 publications

References 18 publications

Two independent pathways of regulated necrosis mediate ischemia–reperfusion injury

Two independent pathways of regulated necrosis mediate ischemia–reperfusion injury

Quercetin induces apoptosis and necroptosis in MCF-7 breast cancer cells

RIP1 Cleavage in the Kinase Domain Regulates TRAIL-Induced NF-κB Activation and Lymphoma Survival

Contact Info

Product

Resources

About